With an estimated 2.7 million new HIV infections in 2008, there is great interest in the potential use of antiretroviral therapy (ART) as a tool for reversing the relentless expansion of the epidemic. The need for highly effective HIV prevention interventions is particularly evident in resource-limited countries with the highest rates of infection. A number of critical questions require timely studies to inform the data-driven assessment and implementation of ART for prevention. Two key questions that figured prominently in debates and presentations at the 18th International AIDS Conference in Vienna (July 2010) included the risk that treated individuals might transmit resistant HIV, and the potential for more risky sexual behavior occurring over the course of life-long treatment. In this competitive continuing renewal of NIAID R01-AI58698, we will leverage our ongoing prospective cohort study of high-risk Kenyan women on ART, established during the first 5-year grant cycle, to provide timely answers to key questions about the use of ART for prevention. In Aim 1, we will develop and validate predictive models for female genital shedding of drug resistant HIV. Aim 2 will include multidisciplinary quantitative and qualitative studies to identify and understand long-term changes in risk behavior in women followed prospectively on ART for up to 10 years. Aim 3 is designed to identify discrete periods when women may be at particularly high risk of transmitting HIV as a result of concurrent ART adherence lapses and more risky sexual behavior. Utilization of our existing cohort will allow us to rapidly implement these studies, providing timely data that will have a lasting impact on global HIV prevention. The results of a randomized trial of ART for prevention in HIV-discordant couples will be available in approximately 5 years. In the interim, much can be gained by using existing cohorts to examine the biological and behavioral changes that predict transmission. Moreover, the predictive models produced by the research proposed in this application will remain a critical tool for optimizing the potential prevention benefits of ART even after the results of the randomized trial of ART for prevention become available. In addition, this research will provide complementary data from a different risk group, and will offer a benchmark for estimating the infectivity of women who could not have been randomly assigned to start or delay ART because they required treatment for advanced HIV. In summary, the proposed research will contribute substantively to HIV-1 prevention science, providing clinically useful tools and data to support clinicians, program managers, and public health officials in realizing the potential benefits of ART for reducing the spread of HIV.